Abstract
It has previously been shown that E3 ubiquitin ligase Casitas B-lineage lymphoma-b (Cbl-b) negatively regulates T-cell activation, but the molecular mechanism(s) underlying this inhibition is not completely defined. In this study, we report that the loss of Cbl-b selectively results in aberrant activation of NF-kappaB upon T-cell antigen receptor (TCR) ligation, which is mediated by phosphatidylinositol 3-kinase (PI3-K)/Akt and protein kinase C-theta (PKC-theta). TCR-induced hyperactivation of Akt in the absence of Cbl-b may potentiate the formation of caspase recruitment domain-containing membrane-associated guanylate kinase protein 1 (CARMA1)-B-cell lymphoma/leukemia 10 (Bcl10)-mucosa-associated lymphatic tissue 1(MALT1) (CBM) complex, which appears to be independent of PKC-theta. Cbl-b associates with PKC-theta upon TCR stimulation and regulates TCR-induced PKC-theta activation via Vav-1, which couples PKC-theta to PI3-K and allows it to be phosphorylated. PKC-theta then couples IkappaB kinases (IKKs) to the CBM complex, resulting in the activation of the IKK complex. Therefore, our data provide the first evidence to demonstrate that the down-regulation of TCR-induced NF-kappaB activation by Cbl-b is mediated coordinately by both Akt-dependent and PKC-theta-dependent signaling pathways in primary T cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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B-Cell CLL-Lymphoma 10 Protein
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CARD Signaling Adaptor Proteins / deficiency
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CARD Signaling Adaptor Proteins / genetics
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CARD Signaling Adaptor Proteins / metabolism
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CD28 Antigens / physiology
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Enzyme Activation
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I-kappa B Kinase / metabolism
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / physiology*
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Lymphocyte Activation / physiology*
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Membrane Microdomains / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes
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NF-kappa B / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase C / deficiency
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Protein Kinase C / genetics
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Protein Kinase C / physiology*
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Protein Kinase C-theta
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Proto-Oncogene Proteins c-akt / physiology*
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Proto-Oncogene Proteins c-cbl / deficiency
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / physiology*
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Proto-Oncogene Proteins c-vav / deficiency
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Proto-Oncogene Proteins c-vav / genetics
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Proto-Oncogene Proteins c-vav / physiology*
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Receptors, Antigen, T-Cell / physiology*
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Signal Transduction / physiology
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T-Lymphocytes / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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B-Cell CLL-Lymphoma 10 Protein
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Bcl10 protein, mouse
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CARD Signaling Adaptor Proteins
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CD28 Antigens
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Card11 protein, mouse
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Cblb protein, mouse
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Isoenzymes
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Multiprotein Complexes
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NF-kappa B
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Proto-Oncogene Proteins c-vav
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Receptors, Antigen, T-Cell
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Vav1 protein, mouse
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Proto-Oncogene Proteins c-cbl
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Phosphatidylinositol 3-Kinases
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Akt1 protein, mouse
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Proto-Oncogene Proteins c-akt
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I-kappa B Kinase
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Prkcq protein, mouse
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Protein Kinase C
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Protein Kinase C-theta